C ₂-Symmetric atropisomeric N-heterocyclic carbene–palladium(II) complexes: synthesis, chiral resolution, and application in the enantioselective α-arylation of amides

Abstract

The concept of atropisomeric N-heterocyclic carbene (NHC)–metal complexes was extended to NHCs possessing a C₂-symmetry and implemented to prepare palladium-based complexes. An in-depth study of the NHC precursors and the screening of various NHC ligands enabled us to circumvent the issue associated with the formation of meso complexes. A set of 8 atropisomeric NHC–palladium complexes were prepared and then obtained with high enantiopurities, thanks to an efficient resolution by chiral HPLC at the preparative scale. These complexes displayed good activity in the intramolecular α-arylation of amides and various cyclic products were isolated with excellent enantioselectivities (up to 98% ee).

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Introduction

Since the seminal work of Arduengo in 1991 disclosing stable N-heterocyclic carbenes (NHCs),¹ NHCs have attracted much attention in particular for their use as ancillary ligands in organometallic chemistry.² Their electronic properties (strong σ-donation and poor π-acceptor characteristics) make them more than simple phosphine mimics and allow the synthesis of a myriad of well-defined transition metal complexes bearing NHC ligands. Many of them exhibit good stability towards air and moisture. The studies on the coordinating properties of NHCs have translated into the development of a wide array of transition-metal-catalyzed transformations among which are the well-known olefin metathesis, palladium-catalyzed cross coupling reactions, and more recently C–H bond activation.³ Therefore, the design of chiral NHC ligands has been the subject of intensive and fruitful research.⁴ So far, two main strategies for the design of chiral monodentate NHC ligands have been explored: (i) the incorporation of chiral patterns as N-substituents, structure A,⁵ including polycyclic structures, structure B ⁶ (Fig. 1.1); (ii) the use of a chiral backbone, structure C,⁷ that can be associated with dissymmetric aryl groups as N-substituents, structure D ⁸ (Fig. 1.2). These two designs can even be combined.^5d,9

Fig. 1 Design of chiral NHC ligands.

Recently, we have developed another design based on a restricted rotation of a dissymmetric N-aryl substituent along the C–N bond. The presence of both methyl groups on the NHC backbone and the metal enabled us to achieve high rotational barrier values and thus obtain configurationally stable complexes (Fig. 1.3).¹⁰ Advantageously, this approach does not require the use of enantiopure synthons since the imidazolium salts, precursors of NHC ligands, are not chiral and the metalation step creates the axis of chirality. Thus, complexes E are obtained as racemic mixtures. Nevertheless, thanks to the high stability of many NHC–metal complexes, in particular enabling purification by silica gel chromatography, a resolution by chiral HPLC at the preparative scale afforded complexes with excellent enantiopurities and high yields. Of note is that this technique of resolution by chiral HPLC¹¹ has been used to prepare various chiral NHC ligands^6d,12 and more recently was applied to obtain enantiopure metal–carbene complexes.¹³ Complexes bearing a C₁-symmetric NHC ligand,¹⁴ for which only one axis of chirality is present, are very convenient to study the rotational barrier values. Thus, they allow fine tuning of the NHC structure in order to obtain atropisomeric metal–NHC complexes displaying good configurational stability.¹⁰ Nonetheless, enantiopure C₁-symmetric Pd–NHC complexes have catalyzed the intramolecular α-arylation of amides with a moderate enantioselectivity (up to 64% ee).^10c

Herein, we disclose the extension of the concept of atropisomeric metal–NHC complexes to C₂-symmetric NHC ligands, which might lead to the formation of meso complexes (meso-F) in addition to both enantiomers (F and ent-F). The enantiopure C₂-symmetric NHC–Pd complexes were successfully tested in the intramolecular α-arylation of amides.

Results and discussion

Several symmetric imidazolium salts 1·X containing methyl substituents at the 4 and 5 positions were synthesized according to literature procedures (Fig. 2).^15,16 Since the imidazolium salt possessing bulky tert-butyl groups as ortho-substituents could not be synthesized, the dissymmetric imidazolium salt 1b·OTf with a tert-butyl group on one side and an iso-propyl group on the other side was prepared. ¹H NMR spectroscopy analyses indicated that these imidazolium salts possess two resonances for the characteristic proton at position 2 accounting for two isomeric forms in solution. An in-depth study on imidazolium salts 1d–f·X demonstrated that the nature of the anion X (Cl, OTf, and BF₄) does not influence significantly the isomeric ratios (Table S1†).¹⁵ However, the NMR solvents used for these analyses led to sharp differences in the isomeric ratios in the case of imidazolium salt 1d·X spanning from 1 : 1.2 in CDCl₃ to 1 : 9 in acetone-d₆. For imidazolium salts 1e·X and 1f·X, the isomeric ratios remain similar whatever the NMR solvent is, 1 : 10 and 1 : 5 respectively. We hypothesized that 1d·X isomers are rotamers while a second ortho-substituent on the N-aryl groups, either a fluorine or a methyl group, leads to an increase in the rotational barrier values about the N–C bonds and gives rise to atropisomers (two diastereomers).

Fig. 2 Imidazolium salts used in this study (X = OTf, Cl and BF₄).

In order to gain insight into the values of the rotational barriers, theoretical calculations were run (Scheme 1).^15,17 According to these calculations, cis-conformations (meso) are more stable than trans-conformations (chiral). As expected, the more energetically favourable rotations take place with the benzhydryl groups on the side of the imidazolium proton (ΔG^≠_(H)) since the methyl groups prevent rotation on the backbone side (ΔG^≠_(BB)). The calculated values indicate that the rotation of N-aryl substituents is not restricted in the case of imidazolium 1d·X (ΔG^≠_(H) = 69.7 kJ mol⁻¹; t_1/2 = 0.1 s at 25 °C). For imidazolium salts 1e·BF₄ and 1f·BF₄, containing additional ortho substituents on the N-aryl groups, either a fluorine or methyl, values of rotational barriers are substantially higher and the rotations of the N-aryl groups appear to be restricted, ΔG^≠_(H) = 108.7 kJ mol⁻¹; t_1/2 = 7 days at 25 °C and ΔG^≠_(H) = 155.9 kJ mol⁻¹; t_1/2 = 4 M years at 25 °C, respectively. In view of these results, we conclude that for imidazolium salts 1e·X and 1f·X, the two isomeric forms observed in solution are diastereomers and can be characterized using a diastereomeric ratio (dr). We attempted to isolate the major diastereomers of imidazolium salts 1e·BF₄ and 1f·BF₄. Diastereomerically pure imidazolium salts were obtained by recrystallization or/and silica gel chromatography.¹⁵ X-ray diffraction analyses of major diastereomers enabled us to unambiguously attribute the trans-conformation to these compounds (Fig. 3) and suggest that the formation of these imidazolium salts occurs under kinetic control.

Scheme 1 Configurational stabilities of imidazolium salts calculated by DFT.

Fig. 3 Ball-and-stick representation of the major diastereomers of the imidazolium salts 1e·BF₄ and 1f·BF₄ (most of the hydrogens have been removed for clarity).

Imidazolium salts 1·X were used to prepare the corresponding Pd(allyl)Cl(NHC) complexes 2 in order to probe the formation of chiral vs. meso complexes, respectively (±)-2 and meso-2 (Table 1). Imidazolium 1a·BF₄ containing isopropyl groups at one of the ortho positions of the N-aryl substituents treated with tBuOK in THF at 25 °C in the presence of [Pd(allyl)Cl]₂ (conditions A) gave complex meso-2a after silica gel purification with a moderate yield (49%, entry 1). The structure of meso-2a was unambiguously determined by single crystal X-ray diffraction studies (Fig. 4) and no trace of the expected chiral complex 2a was detected. The complex formation was repeated at 60 °C and using K₂CO₃ instead of tBuOK (conditions B) according to the procedure disclosed by Nolan and Cazin (entry 2).¹⁸ Complex meso-2a was isolated in a higher yield (78%) but still without formation of (±)-2a. At this stage, we postulated that more hindered ortho-substituents on the aromatic side groups should favor the formation of a chiral complex. Nevertheless, with pre-ligand 1b·OTf, the corresponding complex 2b was obtained with a cis arrangement of the tert-butyl and isopropyl groups, even if the presence of a small amount of trans-2b cannot be ruled out.¹⁵ Of note, complex cis-2b is chiral but can be considered a “pseudo meso” complex. At this stage, we hypothesized that the preferential formation of meso complexes might be the result of an induced dipole-induced dipole attraction involving alkyl groups in the ortho position (London dispersion forces).¹⁹ Thus, we turned our attention toward imidazolium salt 1c·BF₄ containing phenyl groups as ortho-substituents (entries 4 and 5). Conditions A allowed the formation of 2 complexes that could be separated by silica gel chromatography. The ¹H NMR spectrum of one of these complexes exhibited two sets of signals for the allyl pattern due to conformers resulting from the allyl orientation and we attributed them to (±)-2c. Whereas for meso-2c, the plane of symmetry results in only one set of signals for the allylic protons.¹⁵ This statement was confirmed by single crystal X-ray diffraction studies of both complexes (Fig. 4). Under conditions A, the yields of (±)-2c and meso-2c were moderate and the meso complex was formed in higher proportions (entry 4). Conditions B improved the overall yield and the expected complex (±)-2c was found to be the major palladium complex (entry 5). Under conditions B, the benzhydryl containing salt 1d·BF₄ led to the formation of two diastereomers which were separated by silica gel chromatography to give rise to (±)-2d and meso-2d, in respectively 28% and 62% yields (entry 6). The structure of meso-2d was confirmed by single crystal X-ray diffraction (Fig. 4). Because imidazolium salt 1e·BF₄ has been synthesized mainly as the trans diastereomer (dr = 10 : 1), complex meso-2e was not observed and only racemic complex (±)-2e was isolated in good yield (72%, entry 7). When imidazolium salt 1f·BF₄ has been used as a mixture of diastereomers (dr = 5 : 1), the corresponding Pd(allyl)Cl(NHC) complexes (±)-2f and meso-2f were formed in overall good yield (79%) and in a 5 : 1 ratio (entry 8). Unfortunately, both diastereomers could not be efficiently separated by silica gel chromatography. However, when diastereomerically pure 1f·BF₄ was employed, only complex (±)-2f was formed with excellent yield. Remarkably, this experiment was performed on a gram scale.¹⁵

Fig. 4 Ball-and-stick representation of the meso complexes 2a, 2c, 2d and 2f and the chiral complex (±)-2c (most of the hydrogens have been omitted for clarity).

Table 1 Synthesis of Pd(allyl)Cl(NHC) complexes bearing C₂-symmetric NHC ligands^a

Entry	Imidazolium salt 1·X	Conditions	Complex (±)-2		Complex meso-2		Overall yield (ratio (±)/meso)
a Conditions A: [Pd(allyl)Cl]2, (1 equiv.); imidazolium salt 1·X (2.3 equiv.), tBuOK (3 equiv.), THF, 25 °C, 6 h. Conditions B: [Pd(allyl)Cl]2, (1 equiv.); imidazolium salt 1·X (2.3 equiv.), K2CO3 (4.8 equiv.), acetone, 60 °C, 5 h.
1		A	Not observed			49%	49% (<1 : 20)
2		B	Not observed			78%	78% (<1 : 20)
3		A	Trace			87%	87% (<1 : 20)
4		A		18%		31%	49% (1 : 1.5)
5		B		57%		42%	99% (1.35 : 1)
6		B		28%		62%	90% (1 : 2.2)
7		B		72%	Not observed		72% (>20 : 1)
8		B					79% (5 : 1)
9		B		92%	Not observed		92% (>20 : 1)

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Next, we extended the complex synthesis to Pd(cinnamyl)Cl(NHC) 3 using imidazolium tetrafluoroborate 1d–f·BF₄ (Table 2). The treatment of the dimeric [Pd(cinnamyl)Cl]₂ and 1d·BF₄ with K₂CO₃ in acetone at 60 °C gave rise to the sole formation of complex meso-3d (entry 1). The presence of the expected chiral complex could not be detected. This indicates that the nature of the allylic ligand has an influence on the diastereoselectivity of the metalation step; unfortunately, the sterically demanding cinnamyl favours the formation of the achiral complex. Configurationally stable imidazolium salts 1e·BF₄ and 1f·BF₄ enabled us to circumvent this issue. Solely complex (±)-3e was obtained starting from 1e·BF₄ (dr = 10 : 1) with a moderate yield (68%, entry 2). As using 1f·BF₄ with a 5 : 1 diastereomeric ratio resulted in an inseparable mixture of complexes (±)-3f and meso-3f with a ratio 5 : 1 (entry 3), diastereomerically pure 1f·BF₄ allowed the single formation of the chiral complex (±)-3f with excellent yield (entry 4). Following the same protocol, chiral complex (±)-4f containing a tert-butyl-indenyl group as an ancillary ligand was prepared in moderate yield starting from diastereomerically pure imidazolium salt 1f·BF₄ (Scheme 2).

Scheme 2 Preparation of the Pd(tBu-indenyl)Cl(NHC) complex 4f.

Table 2 Synthesis of Pd(cinnamyl)Cl(NHC) complexes bearing C₂-symmetric NHC ligands

Entry	Imidazolium salt 1·BF4	Complex (±)-3		Complex meso-3		Overall yield (ratio (±)/meso)
1		Not observed			78%	78% (<1 : 20)
2			68%	Not observed		68% (>20 : 1)
3						82% (5 : 1)
4			90%	Not observed		90% (>20 : 1)

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Having a series of 8 chiral palladium–NHC complexes, we studied the racemate resolution by chiral HPLC at a preparative scale (Scheme 3). Various chiral columns were screened and the detection of enantiomers was performed with an UV–vis detector connected to a circular dichroism detector, giving the CD sign at 254 nm for each enantiomer. The chiralpak IG column enabled the efficient resolution of all palladium complexes.¹⁵ Using a 1 cm diameter column, batches from 15 to 850 mg were purified in several hours affording both enantiomers with excellent enantiopurities, superior to 99.5% ee for most of the complexes. Yields of the resolution step span from 23 to 97% as a function of the complex.

Scheme 3 Resolution of racemic complexes by cHPLC at a preparative scale.

The configurational stability of these chiral complexes was found to be good, as attempts to determine experimentally the diastereomerization barriers require prolonged heating at 130 °C or at a higher temperature which causes a complex degradation faster than the diastereomerization process.

The low stability of complex (±)-2c in solution and in the solid state explains the low yields of enantiopure complexes (29 and 21%). To illustrate the efficiency of the resolution by chiral HPLC at a preparative scale, a batch of 850 mg of (±)-2f afforded 420 mg (49%) and 401 mg (48%) of both enantiomers after 45 injections every 5 min (about 4 h for the complete resolution). Crystals of first eluted complexes cis-2b and 2e and second eluted complexes 2d and 2f suitable for single crystal X-ray diffraction were obtained and allowed the determination of their absolute configuration. Of note, the modification of the absolute configuration between complexes 2e and 2f is the result of priority changes to assess the stereodescriptors.

UV-vis and ECD spectra for both enantiomers for all complexes have been recorded in acetonitrile solutions. Individual ECD spectra, reported in the ESI,† showed expected mirror images for both enantiomers.¹⁵ The comparison of ECD spectra with those of complexes that have been studied by X-ray crystallography was used to assign absolute configurations of all complexes. As an example, ECD spectra of the 2^nd eluted complexes 2f, 3f and 4f, depicted in Fig. 5, show a similar shape for complexes 2f and 3f with a positive ECD-active band between 195 and 200 nm and a negative ECD-active band between 220 and 230 nm. Thus, allyl- and cinnamyl-complexes 2f and 3f possess the same spatial conformation. tert-Butyl-indenyl complex 4f displays an ECD spectrum being the mirror image of those of complexes 2f and 3f indicating an inversion of the elution order, although the optical rotation values of all 2^nd eluted complexes are positive (+). Enantiopure complexes 2c and 4f display optical rotation values of high magnitude at several wavelengths ((±)-2c, [α]²⁵₅₈₉ = ± 300; (±)-4f, [α]²⁵₅₈₉ = ± 740).

Fig. 5 ECD spectra of the second eluted complexes (+)-2f, (+)-3f and (+)-4f.

Enantiopure complexes were tested in the asymmetric intramolecular α-arylation of amides using amide 5a as the benchmark substrate (Table 3).^8c,20 Reactions were performed at 40 °C in DME using potassium tert-butoxide as the base. Neither complex cis-2b due to its “pseudo meso” structure nor 2c due to its poor stability was evaluated. Complex (+)-(R_a,R_a)-2d catalyzed the formation of product 6a with a moderate yield (44%) and a good enantiomeric excess (77%, entry 1). In comparison, (−)-(R_a,R_a)-2e allowed to improve the isolated yield with a slight decrease of the enantioinduction (72%, entry 2).

Table 3 Catalysts screening for the palladium-catalyzed intermolecular α-arylation of amide 6a

Entry	Catalyst	T (°C)	Yield^a (%)	ee^b (%)
a Isolated yield. b Determnined by chiral HPLC analysis. c Reaction duration 5 h (DME = 1,2-dimethoxyethane).
1	(+)-(Ra,Ra)-2d	40	44	77 (S)
2	(−)-(Ra,Ra)-2e	40	73	72 (R)
3	(−)-(Sa,Sa)-2f	40	85	95 (R)
4	(+)-(Ra,Ra)-2f	40	84	95 (S)
5	meso-2f	40	54	—
6	(−)-(Ra,Ra)-3e	40	65	77 (R)
7	(+)-(Ra,Ra)-3f	40	86	92 (S)
8	(−)-(Ra,Ra)-4f	40	93	92 (S)
9	(+)-(Ra,Ra)-2f	25	8	92 (S)
10	(+)-(Ra,Ra)-2f	60	84	95 (S)
11^c	(+)-(Ra,Ra)-2f	80	87	95 (S)

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Enantiopure complexes 2f enabled us to obtain both good activity and an excellent enantioselectivity (95% ee, entries 3 and 4). From the efficiency point of view, catalysts containing bulkier NHC ligands display a high activity since they favor reductive elimination. Of note, we noticed that pre-catalyst meso-2f was significantly less efficient than chiral analogs (entry 5). It seems that having the sterically hindered benzhydryl groups on only one side of the NHC is less favorable to boosting the reductive elimination. This observation is in sharp contrast with the study disclosed by Kündig.²⁰ⁱ Based on DFT calculations, it has been proposed that oxidative addition is the rate-determining step. Nevertheless, a recent theoretical study on palladium-catalyzed α-arylation of ketones with phosphine ligands suggested that reductive elimination is the rate-limiting step.²¹ As expected, the nature of the allyl derivative ligand has no meaningful influence on the enantioselectivity (72% ee, entry 2 vs. 77% ee, entry 6) (95% ee, entries 3 and 4 vs. 92% ee, entry 7 vs. 92%, entry 8) since the generated catalytic species is the same. As isolated yields are good to excellent, the effect of the nature of the allyl derivative ligand on catalytic activity cannot be confidently addressed. At 25 °C, using (+)-(R_a,R_a)-2f, only a tiny amount of 6a was isolated with a similar enantiomeric excess (92%, entry 9). At higher temperatures, 60 or 80 °C, identical ees were measured (entries 10 and 11). This observation proves that not only pre-catalysts but also catalytic species possess excellent configuration stability.

The scope of the intramolecular α-arylation of amides was studied with several substrates using enantiopure complexes 2f, either (+)-(R_a,R_a)-2f or (−)-(S_a,S_a)-2f (Scheme 4). Absolute configurations of products were determined based on the work of Kündig^20b,i or by analogy and were tentative. With amide 5a(Cl), the chlorinated analogue of 5a, a similar yield of 6a(Cl) was isolated possessing the same enantiopurity. The reaction was complete after 20 h at 40 °C with 5b containing a methoxy group at the para position of the bromine. Substrates bearing electron-donating and electron-withdrawing groups at the meta position, OMe (5c) and OCF₃ (5d) respectively, were found less reactive and required either a prolonged reaction time (60 h) or an increase of the reaction temperature to 60 °C to reach completion. All these products were isolated with enantiomeric excesses superior to 90% ee. With substrates derived from ibuprofen, ketoprofen and naproxen, products 6e, 6f and 6g, respectively, were isolated with excellent yields and enantioselectivities. A slightly higher enantiomeric excess was obtained with N-benzyl-substituted substrate 5h (6h, 98% ee) compared to N-methyl-substituted substrate 5a. The nature of the alkyl group of the stereogenic center has an influence on the enantioselectivity related to its steric bulk: methyl (6a, 95% ee), ethyl (6i, 87% ee) and cyclopentyl (6j, 45% ee). Of note, substrate 5j has been previously investigated by Trapp and coworkers and up to 55% ee for 6j was reported.^20h We screened again several enantiopure atropisomeric Pd–NHC complexes and using the fluorine containing complex (−)-(R_a,R_a)-2e the enantiomeric excess was increased up to 72% ee. Substrate 5k containing a methyl and an allyl group on the stereogenic center represents a very challenging substrate. Despite the full conversion of the substrate at 60 °C and the good isolated yield of product 6k, only a low enantiomeric excess (24% ee) was reached. To our delight, the highly enantio-enriched spiro compound 6l (92% ee) was isolated in high yield (92%) under the same conditions with catalyst (+)-(R_a,R_a)-2f.

Scheme 4 Scope investigation on asymmetric α-arylation of amides 5 (absolute configurations were assigned by analogy and were tentative).

Conclusions

In conclusion, we successfully applied the concept of atropisomeric NHC–metal complexes to C₂-symmetric NHC ligands and implemented it into the preparation of chiral palladium complexes. The use of imidazolium salts with unrestricted rotation axes (rotamers) as NHC precursors gave mostly meso palladium complexes, probably as thermodynamic products. To circumvent this issue, imidazolium salts containing additional ortho-substituents (F or Me) were found to be conformationally stable and have been prepared mainly as chiral, yet racemic. So far, we could not unambiguously point out the parameters governing the formation of either meso or chiral complexes; the working hypothesis involving London dispersion forces could not be clearly demonstrated. Thus, several chiral palladium(II) complexes containing an allyl, a cinnamyl or a tBu-indenyl group as an ancillary ligand were synthesized. These racemic complexes exhibited good chemical stability and could be resolved using chiral HPLC at the preparative scale. Both enantiomers of each palladium complex were obtained with excellent enantiopurities and overall good yields and this strategy could be efficiently implemented up to 850 mg scale. The absolute configuration of the enantiopure complexes was determined by single crystal X-ray diffraction and comparison of the ECD spectra. Enantiopure complexes were tested in the intramolecular α-arylation of amides and excellent enantioselectivities (up to 98% ee) can be achieved with some of the enantiopure atropisomeric palladium complexes that have been designed and prepared. This finding is in sharp contrast to results obtained with analogue C₁-symmetric NHC–palladium complexes (up to 54% ee).^10b Having in hand a new and efficient design of chiral catalysts, further development of new enantioselective reactions is currently underway in our laboratory.

Author contributions

Lingyu Kong and Yajie Chou: organic synthesis, complex preparation, and asymmetric catalysis; Muriel Albalat, Marion Jean, and Nicolas Vanthuyne: chiral HPLC analyses, preparative chiral HPLC, determination of the chiroptic properties, and ee measurements; Paola Nava and Stéphane Humbel: theoretical calculations; Hervé Clavier: conceptualization, writing – reviewing and editing, and supervision.

Conflicts of interest

The authors declare that there are no conflicts of interest.

Acknowledgements

We are grateful to the CNRS, Aix-Marseille Université and the ECM. L. K. and Y. C. thank the China Scholarship Council for Ph.D. grants. We acknowledge the Agence Nationale de la Recherche (ANR-20-CE07-0030 cResolu). We thank the Spectropole, Fédération des Sciences de Marseille, in particular, Dr Roseline Rosas for VT-NMR spectroscopy, Dr Michel Giorgi for DRX, and Dr Valérie Monnier for HRMS as well as Arnaud Treuvey (ECM) for IR spectroscopy. Umicore AG & Co is acknowledged for a generous gift of complexes. Calcul Intensif d'Aix-Marseille is acknowledged for granting access to its high performance computing resources (project b289).

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9. (a) A. Alexakis, C. L. Winn, F. Guillen, J. Pytkowicz, S. Roland and P. Mangeney, Adv. Synth. Catal., 2003, 345, 345–348; (b) D. Baskakov, W. A. Herrmann, E. Herdtweck and S. D. Hoffmann, Organometallics, 2007, 26, 626–632; (c) L. Liu, N. Ishida, S. Ashida and M. Murakami, Org. Lett., 2011, 13, 1666–1669.
10. (a) L. Kong, J. Morvan, D. Pichon, M. Joan, M. Albalat, T. Vives, S. Colombel-Rouen, M. Giorgi, V. Dorcet, T. Roisnel, C. Crévisy, D. Nuel, P. Nava, S. Humbel, N. Vanthuyne, M. Mauduit and H. Clavier, J. Am. Chem. Soc., 2020, 142, 93–98; (b) L. Kong, Y. Chou, M. Jean, M. Albalat, N. Vanthuyne, P. Nava, S. Humbel and H. Clavier, Adv. Synth. Catal., 2021, 363, 4229–4238; (c) M. Savchuk, L. Bocquin, M. Albalat, M. Jean, N. Vanthuyne, P. Nava, S. Humbel, D. Hérault and H. Clavier, Chirality, 2022, 33, 13–26; (d) J. Morvan, D. Bouëtard, L. Kong, Y. Chou, T. Vives, M. Albalat, T. Roisnel, C. Crévisy, P. Nava, S. Humbel, N. Vanthuyne, H. Clavier and M. Mauduit, Chem. – Eur. J., 2023, 29, e202300341.
11. For a comprehensive review on enantiomer resolution by chiral HPLC, see: Y. Okamoto and T. Ikai, Chem. Soc. Rev., 2008, 37, 2593–2608.
12. (a) V. Göker, S. R. Kohl, F. Rominger, G. Meyer-Eppler, L. Volbach, G. Schnakenburg, A. Lützen and A. S. K. Hashmi, J. Organomet. Chem., 2015, 795, 45–52; (b) F. Grande-Carmona, J. Iglesias-Sigüenza, E. Álvarez, E. Díez, R. Fernàndez and J. M. Lassaletta, Organometallics, 2015, 34, 5073–5080; (c) V. Paradiso, S. Menta, M. Pierini, G. Della Sala, A. Ciogli and F. Grisi, Catalysts, 2016, 6, 177–188; (d) Z. Szabó, A. Paczal, T. Kovács, A. Mándi, A. Kotschy and T. Kurtán, Int. J. Mol. Sci., 2022, 23, 3471.
13. Representative examples: (a) N. Hellou, C. Jahier-Diallo, O. Baslé, M. Srebro-Hooper, L. Toupet, T. Roisnel, E. Caytan, C. Roussel, N. Vanthuyne, J. Autschbach, M. Mauduit and J. Crassous, Chem. Commun., 2016, 52, 9243–9246; (b) J. Morvan, F. Vermersch, Z. Zhang, L. Falivene, T. Vives, V. Dorcet, T. Roisnel, C. Crévisy, L. Cavallo, N. Vanthuyne, G. Bertrand, R. Jazzar and M. Mauduit, J. Am. Chem. Soc., 2020, 142, 19895–19901; (c) H. Yi, K. M. Osten, T. I. Levchenko, A. J. Veinot, Y. Aramaki, T. Ooi, M. Nambo and C. M. Crudden, Chem. Sci., 2021, 12, 10436–10440; (d) T. Martinez, A. Vanitcha, C. Troufflard, N. Vanthuyne, J. Forté, G. Gontard, G. Lemière, V. Mouriès-Mansuy and L. Fensterbank, Angew. Chem., Int. Ed., 2021, 60, 19879–19888; (e) L. Pallova, L. Abella, M. Jean, N. Vanthuyne, C. Barthes, L. Vendier, J. Autschbach, J. Crassous, S. Bastin and V. Cesar, Chem. – Eur. J., 2022, 28, e202200166.
14. This type of NHC ligands, for which the two N-substituents are different, is sometimes named unsymmetrical NHC (uNHC), even if “unsymmetrical” is inappropriate and not defined in the IUPAC nomenclature.
15. For details, see ESI.†.
16. (a) K. Hirano, S. Urban, C. Wang and F. Glorius, Org. Lett., 2009, 11, 1019–1022; (b) J. Zhang, J. Fu, X. Su, X. Wang, S. Song and M. Shi, Chem. – Asian J., 2013, 8, 552–555.
17. For rare publications disclosing theoretical calculations on N-aryl group rotations, see: (a) X. Luan, R. Mariz, M. Gatti, C. Costabile, A. Poater, L. Cavallo, A. Linden and R. Dorta, J. Am. Chem. Soc., 2008, 130, 6848–6858; (b) G. Laidlaw, S. H. Wood, A. R. Kennedy and D. J. Nelson, Z. Anorg. Allg. Chem., 2019, 645, 105–112.
18. C. M. Zinser, F. Nahra, M. Brill, R. E. Meadows, D. B. Cordes, A. M. Z. Slawin, S. P. Nolan and C. S. J. Cazin, Chem. Commun., 2017, 53, 7990–7993.
19. J. P. Wagner and P. R. Schreiner, Angew. Chem., Int. Ed., 2015, 54, 12274–12296.
20. For selected references on the palladium-catalyzed enantioselective intramolecular α-arylation of amides with chiral NHC ligands, see: (a) S. Lee and J. F. Hartwig, J. Org. Chem., 2001, 66, 3402–3415; (b) E. P. Kündig, T. M. Seidel, Y.-X. Jia and G. Bernardinelli, Angew. Chem., Int. Ed., 2007, 46, 8484–8487; (c) Y.-X. Jia, J. M. Hillgren, E. L. Watson, S. P. Marsden and E. P. Kündig, Chem. Commun., 2008, 4040–4042; (d) S. Würtz, C. Lohre, R. Fröhlich, K. Bergander and F. Glorius, J. Am. Chem. Soc., 2009, 131, 8344–8345; (e) X. Luan, L. Wu, E. Drinkel, R. Mariz, M. Gatti and R. Dorta, Org. Lett., 2010, 12, 1912–1915; (f) L. Liu, N. Ishida, S. Ashida and M. Murakami, Org. Lett., 2011, 13, 1666–1669; (g) L. Wu, L. Falivene, E. Drinkel, S. Grant, A. Linden, L. Cavallo and R. Dorta, Angew. Chem., Int. Ed., 2012, 51, 2870–2873; (h) M. J. Spallek, D. Riedel, F. Rominger, A. S. K. Hashmi and O. Trapp, Organometallics, 2012, 31, 1127–1132; (i) D. Katayev, Y.-X. Jia, A. K. Sharma, D. Banerjee, C. Besnard, R. B. Sunoj and E. P. Kündig, Chem. – Eur. J., 2013, 19, 11916–11927; (j) C. Xu, Y. Feng, L.-R. Wang, W.-P. Ma, Y.-M. He and Q.-H. Fan, Organometallics, 2020, 39, 1945–1960.
21. S. Tcyrulnikov and M. C. Kozlowski, J. Org. Chem., 2020, 85, 3465–3472.

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Footnotes

† Electronic supplementary information (ESI) available. CCDC 2049184–2049186; 2250208-2250215. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d3dt01182h

‡ These authors contributed equally.

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